Kv3.1 Voltage-gated Potassium Channels Modulate Anxiety-like Behaviors in Female Mice.

Inhibitory parvalbumin (PV) interneurons regulate the activity of neural circuits within brain regions involved in emotional processing, including the prefrontal cortex (PFC). Recently, rodent studies have implicated a stress-induced increase in prefrontal PV neuron activity in the development of anxiety behaviors, particularly in females. However, the mechanisms through which stress increases activity of prefrontal PV neurons remain unknown. The fast-spiking properties of PV neurons in part come from their expression of voltage-gated potassium (K+) ion channels, particularly Kv3.1 channels. We therefore suggest that stress-induced changes in Kv3.1 channels contribute to the appearance of an anxious phenotype following chronic stress in female mice. Here, we first showed that unpredictable chronic mild stress (UCMS) increased expression of Kv3.1 channels on prefrontal PV neurons in female mice, a potential mechanism underlying the previously observed hyperactivity of these neurons after stress. We then showed that female mice deficient in Kv3.1 channels displayed resilience to UCMS-induced anxiety-like behaviors. Altogether, our findings implicate Kv3.1 channels in the development of anxiety-like behaviors following UCMS, particularly in females, providing a novel mechanism to understand sex-specific vulnerabilities to stress-induced psychopathologies.

Sex-Specific Timelines for Adaptations of Prefrontal Parvalbumin Neurons in Response to Stress and Changes in Anxiety- and Depressive-Like Behaviors.

Women are twice as likely as men to experience emotional dysregulation after stress, resulting in substantially higher psychopathology for equivalent lifetime stress exposure, yet the mechanisms underlying this vulnerability remain unknown. Studies suggest changes in medial prefrontal cortex (mPFC) activity as a potential contributor. Whether maladaptive changes in inhibitory interneurons participate in this process, and whether adaptations in response to stress differ between men and women, producing sex-specific changes in emotional behaviors and mPFC activity, remained undetermined. This study examined whether unpredictable chronic mild stress (UCMS) in mice differentially alters behavior and mPFC parvalbumin (PV) interneuron activity by sex, and whether the activity of these neurons drives sex-specific behavioral changes. Four weeks of UCMS increased anxiety-like and depressive-like behaviors associated with FosB activation in mPFC PV neurons, particularly in females. After 8 weeks of UCMS, both sexes displayed these behavioral and neural changes. Chemogenetic activation of PV neurons in UCMS-exposed and nonstressed males induced significant changes in anxiety-like behaviors. Importantly, patch-clamp electrophysiology demonstrated altered excitability and basic neural properties on the same timeline as the emergence of behavioral effects: changes in females after 4 weeks and in males after 8 weeks of UCMS. These findings show, for the first time, that sex-specific changes in the excitability of prefrontal PV neurons parallel the emergence of anxiety-like behavior, revealing a potential novel mechanism underlying the enhanced vulnerability of females to stress-induced psychopathology and supporting further investigation of this neuronal population to identify new therapeutic targets for stress disorders.

Prepubertal ovariectomy confers resilience to stress-induced anxiety in adult female mice.

The increased vulnerability to stress-induced neuropsychiatric disorders in women, including anxiety disorders, does not emerge until pubertal onset, suggesting a role for ovarian hormones in organizing sex-specific vulnerability to anxiety. Parvalbumin (PV) interneurons in the prefrontal cortex are a potential target for these ovarian hormones. PV+ interneurons undergo maturation during the adolescent period and have been shown to be sensitive to stress and to mediate stress-induced anxiety in female mice. To test the idea that ovarian hormones at puberty are necessary for the acquisition of sensitivity to stress, hypothetically driving the response of PV+ interneurons to stress, we performed ovariectomy or sham surgery before pubertal onset in female mice. These mice then were exposed to four weeks of unpredictable chronic mild stress in adulthood. We then assessed anxiety-like behavior and PV/FosB colocalization in the medial PFC. Additionally, we assessed stress-induced anxiety-like behavior in female mice following ovariectomy in adulthood to determine if puberty is a sensitive period for ovarian hormones in mediating vulnerability to stress. We found that prepubertal ovariectomy protects against the development of anxiety-like behavior in adulthood, an effect not found following ovariectomy in adulthood. This effect may be independent of ovarian hormones on prefrontal PV+ interneurons response to stress.

The glucocorticoid footprint on the memory engram.

The complexity of the classical inverted U-shaped relationship between cortisol levels and responses transposable to stress reactivity has led to an incomplete understanding of the mechanisms enabling healthy and toxic effects of stress on brain and behavior. A clearer, more detailed, picture of those relationships can be obtained by integrating cortisol effects on large-scale brain networks, in particular, by focusing on neural network configurations from the perspective of inhibition and excitation. A unifying view of Semon and Hebb's theories of cellular memory links the biophysical and metabolic changes in neuronal ensembles to the strengthening of collective synapses. In that sense, the neuronal capacity to record, store, and retrieve information directly relates to the adaptive capacity of its connectivity and metabolic reserves. Here, we use task-activated cell ensembles or simply engram cells as an example to demonstrate that the adaptive behavioral responses to stress result from collective synapse strength within and across networks of interneurons and excitatory ones.

Age- and sex-specific effects of stress on parvalbumin interneurons in preclinical models: Relevance to sex differences in clinical neuropsychiatric and neurodevelopmental disorders.

Stress is a major risk factor for neurodevelopmental and neuropsychiatric disorders, with the capacity to impact susceptibility to disease as well as long-term neurobiological and behavioral outcomes. Parvalbumin (PV) interneurons, the most prominent subtype of GABAergic interneurons in the cortex, are uniquely responsive to stress due to their protracted development throughout the highly plastic neonatal period and into puberty and adolescence. Additionally, PV + interneurons appear to respond to stress in a sex-specific manner. This review aims to discuss existing preclinical studies that support our overall hypothesis that the sex-and age-specific impacts of stress on PV + interneurons contribute to differences in individual vulnerability to stress across the lifespan, particularly in regard to sex differences in the diagnostic rate of neurodevelopmental and neuropsychiatric diseases in clinical populations. We also emphasize the importance of studying sex as a biological variable to fully understand the mechanistic and behavioral differences between males and females in models of neuropsychiatric disease.

Social impairments in mice lacking the voltage-gated potassium channel Kv3.1.

Parvalbumin (PV)-expressing neurons have been implicated in the pathology of autism spectrum disorders (ASD). Loss of PV expression and/or reduced number of PV-expressing neurons have been reported not only in genetic and environmental rodent models of ASD, but also in post-mortem analyses of brain tissues from ASD vs. healthy control human subjects. PV-expressing neurons play a pivotal role in the maintenance of the balance between excitation and inhibition within neural circuits in part because of their fast-spiking properties. Their high firing rate is mostly regulated by the voltage-gated potassium channel Kv3.1. It is yet unknown whether disturbances in the electrophysiological properties of PV-expressing neurons per se can lead to behavioral disturbances. We assessed locomotor activity, social interaction, recognition and memory, and stereotypic behaviors in Kv3.1 wild-type (WT) and knockout (KO) mice. We then used Western Blot analyses to measure the impact of Kv3.1 deficiency on markers of GABA transmission (PV and GAD67) and neural circuit activity (Egr1). Deficiency in Kv3.1 channel is sufficient to induce social deficits, hyperactivity and stereotypic behaviors. These behavioral changes were independent of changes in GAD67 levels and associated with increased levels of PV protein in the prefrontal cortex and striatum. These findings reveal that a loss of PV expression is not a necessary factor to induce an ASD-like phenotype in mice and support the need for further investigation to fully understand the contribution of PV-expressing neurons to ASD pathology.

Sex Differences in the Sustained Effects of Ketamine on Resilience to Chronic Stress.

Exposure to stress is recognized to be a triggering factor in several mood disorders, including depression and anxiety. There is very little understanding of why female subjects have a significantly higher risk for these conditions than males. Recent findings in male rodents indicated that prophylactic ketamine can prevent the development of a stress-induced depressive-like phenotype, providing a pharmacological tool to study the mechanisms underlying stress resilience. Unfortunately, none of these studies incorporated female subjects, nor did they provide a mechanistic understanding of the effects of ketamine on stress resilience. Our previous work identified the prefrontal glutamatergic and parvalbumin (PV) systems as potential molecular mechanisms underlying sex differences in susceptibility to stress-induced emotional deregulations. To further address this point, we treated male and female mice with a single dose of ketamine before exposure to a chronic stress paradigm to determine whether stress-resilience induced by a pre-exposure to ketamine is similar in males and females and whether modulation of the prefrontal glutamatergic and PV systems by ketamine is associated with these behavioral effects. Ketamine prevented chronic stress-induced changes in behaviors in males, which was associated with a reduction in expression of PV and the NMDA receptor NR1 subunit. Ketamine did not protect females against the effects of chronic stress and did not change significantly prefrontal gene expression. Our data highlight fundamental sex differences in the sustained effects of ketamine. They also further implicate prefrontal glutamatergic transmission and PV in resilience to chronic stress.

Prefrontal parvalbumin cells are sensitive to stress and mediate anxiety-related behaviors in female mice.

Reduced activity of the prefrontal cortex (PFC) is seen in mood disorders including depression and anxiety. The mechanisms of this hypofrontality remain unclear. Because of their specific physiological properties, parvalbumin-expressing (PV+) inhibitory interneurons contribute to the overall activity of the PFC. Our recent work using a chronic stress mouse model showed that stress-induced increases in prefrontal PV expression correlates with increased anxiety-like behaviors in female mice. Our goal is now to provide a causal relationship between changes in prefrontal PV+ cells and changes in emotional behaviors in mice. We first show that, in addition to increasing overall level of PV expression, chronic stress increases the activity of prefrontal PV+ cells. We then used a chemogenetic approach to mimic the effects of chronic stress and specifically increase the activity of prefrontal PV+ cells. We observed that chemogenetic activation of PV+ cells caused an overall reduction in prefrontal activity, and that chronic activation of PV+ cells lead to increased anxiety-related behaviors in female mice only. These results demonstrate that activity of prefrontal PV+ cells could represent a novel sex-specific modulator of anxiety-related behaviors, potentially through changes in overall prefrontal activity. The findings also support the idea that prefrontal PV+ cells are worth further investigation to better understand mood disorders that are more prevalent in female populations.

Region-specific interneuron demyelination and heightened anxiety-like behavior induced by adolescent binge alcohol treatment.

Adolescent binge drinking represents a major public health challenge and can lead to persistent neurological and mental conditions, but the underlying pathogenic mechanisms remain poorly understood. Using a mouse model of adolescent binge ethanol treatment (ABET), we found that this treatment induced behavioral changes associated with demyelination in different brain regions. After ABET, adolescent mice exhibited anxiogenic behaviors with no change in locomotion on the elevated plus maze, and impaired spatial memory indicated by a significant reduction in spontaneous alternation in the Y maze test. Both effects persisted into adulthood. Anatomical studies further showed that ABET induced a significant reduction of parvalbumin-positive (PV+) GABAergic interneurons and myelin density in the hippocampus and medial prefrontal cortex (mPFC). While these deficits in PV+ interneurons and myelin persisted into early adulthood in the hippocampus, the myelin density recovered in the mPFC. Moreover, whereas ABET mainly damaged myelin of PV+ axons in the hippocampus, it primarily damaged myelin of PV-negative axons in the mPFC. Thus, our findings reveal that an adolescent binge alcohol treatment regimen disrupts spatial working memory, increases anxiety-like behaviors, and exerts unique temporal and spatial patterns of gray matter demyelination in the hippocampus and mPFC.

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition.

Chronic stress-induced emotional disorders like anxiety and depression involve imbalances between the excitatory glutamatergic system and the inhibitory GABAergic system in the prefrontal cortex (PFC). However, the precise nature and trajectory of excitatory/inhibitory (E/I) imbalances in these conditions is not clear, with the literature reporting glutamatergic and GABAergic findings that are at times contradictory and inconclusive. Here we propose and discuss the hypothesis that chronic stress-induced emotional dysfunction involves hypoactivity of the PFC due to increased inhibition. We will also discuss E/I imbalances in the context of sex differences. In this review, we will synthesize research about how glutamatergic and GABAergic systems are perturbed by chronic stress and in related emotional disorders like anxiety and depression and propose ideas for reconciling contradictory findings in support of the hypothesis of over-inhibition. We will also discuss evidence for how aspects of the GABAergic system such as parvalbumin (PV) cells can be targeted therapeutically for reinstating activity and plasticity in the PFC and treating stress-related disorders.

Downregulation of Npas4 in parvalbumin interneurons and cognitive deficits after neonatal NMDA receptor blockade: relevance for schizophrenia.

Dysfunction of prefrontal parvalbumin (PV+) interneurons has been linked with severe cognitive deficits as observed in several neurodevelopmental disorders including schizophrenia. However, whether a specific aspect of PV+ neurons deregulation, or a specific molecular mechanism within PV+ neurons is responsible for cognitive deficits and other behavioral impairments remain to be determined. Here, we induced cognitive deficits and altered the prefrontal PV system in mice by exposing them neonatally to the NMDA receptor antagonist ketamine. We observed that the cognitive deficits and hyperactivity induced by neonatal ketamine were associated with a downregulation of Npas4 expression specifically in PV+ neurons. To determine whether Npas4 downregulation-induced dysfunction of PV+ neurons could be a molecular contributor to the cognitive and behavioral impairments reported after neonatal ketamine, we used a transgenic Cre-Lox approach. Reduced Npas4 expression within PV+ neurons replicates deficits in short-term memory observed after neonatal ketamine, but does not reproduce disturbances in general activity. Our data show for the first time that the brain-specific transcription factor Npas4 may be an important contributor to PV+ neurons dysfunction in neurodevelopmental disorders, and thereby could contribute to the cognitive deficits observed in diseases characterized by abnormal functioning of PV+ neurons such as schizophrenia. These findings provide a potential novel therapeutic target to rescue the cognitive impairments of schizophrenia that remain to date unresponsive to treatments.

Sex Differences in Risk and Resilience: Stress Effects on the Neural Substrates of Emotion and Motivation.

Risk for stress-sensitive psychopathologies differs in men and women, yet little is known about sex-dependent effects of stress on cellular structure and function in corticolimbic regions implicated in these disorders. Determining how stress influences these regions in males and females will deepen our understanding of the mechanisms underlying sex-biased psychopathology. Here, we discuss sex differences in CRF regulation of arousal and cognition, glucocorticoid modulation of amygdalar physiology and alcohol consumption, the age-dependent impact of social stress on prefrontal pyramidal cell excitability, stress effects on the prefrontal parvalbumin system in relation to emotional behaviors, contributions of stress and gonadal hormones to stress effects on prefrontal glia, and alterations in corticolimbic structure and function after cessation of chronic stress. These studies demonstrate that, while sex differences in stress effects may be nuanced, nonuniform, and nonlinear, investigations of these differences are nonetheless critical for developing effective, sex-specific treatments for psychological disorders.

Adolescent Stress Disrupts the Maturation of Anxiety-related Behaviors and Alters the Developmental Trajectory of the Prefrontal Cortex in a Sex- and Age-specific Manner.

Adolescence is a window of vulnerability to environmental factors such as chronic stress that can disrupt brain development and cause long-lasting behavioral dysfunction, as seen in disorders like depression, anxiety, and schizophrenia. There are also sex differences in the prevalence of these disorders across the lifespan. However, the mechanisms of how adolescent stress contributes to neuropsychiatric phenotypes are not well understood, nor are the mediating effects of sex. We hypothesize that adolescent stress disrupts the γ-aminobutyric acid (GABA) system in the prefrontal cortex (PFC) in a sex-specific manner, as this system matures during adolescence and plays an important role in cognitive and emotional functioning. We exposed male and female mice to unpredictable chronic mild stress (UCMS) during adolescence (post-natal day [PND] 28-42). One cohort underwent testing for PFC-related behavioral and molecular changes 24 h following the cessation of stress (late adolescence); a separate cohort was tested approximately 2.5 weeks after the end of UCMS (adulthood). We observed an age-related decline in anxiety-like behaviors in control mice, while mice stressed in adolescence showed elevated anxiety-like behaviors in both adolescence and adulthood. PFC-dependent cognitive functioning was also impaired in adult males stressed in adolescence. Adolescent stress disrupted expression patterns of parvalbumin (PV) and perineuronal nets (PNNs) in the PFC, as well as NMDA receptor subunit composition, in a sex- and age-specific manner. The findings presented here contribute to understanding how adolescent stress may lead to neuropsychiatric disorders such as anxiety by disrupting the development of the PFC and emotional behaviors.

Changes in the Prefrontal Glutamatergic and Parvalbumin Systems of Mice Exposed to Unpredictable Chronic Stress.

The prefrontal cortex (PFC) is highly sensitive to the effects of stress, a known risk factor of mood disorders including anxiety and depression. Abnormalities in PFC functioning have been well described in humans displaying stress-induced depressive symptoms, and hypoactivity of the PFC is now recognized to be a key feature of the depressed brain. However, little is known about the causes and mechanisms leading to this altered prefrontal functional activity in the context of stress-related mood disorders. We previously showed that unpredictable chronic mild stress (UCMS) in mice increases prefrontal expression of parvalbumin (PV), an activity-dependent calcium-binding albumin protein expressed in a specific subtype of GABAergic neurons, highlighting a potential mechanism through which chronic stress leads to hypofunction of the PFC. In this study, we aimed to investigate the mechanisms by which chronic stress alters the prefrontal GABA system. We hypothesized that chronic stress-induced enhancement of glutamatergic transmission in the PFC is a crucial contributing factor to changes within the prefrontal GABAergic and, specifically, PV system. BALB/c male and female mice were exposed to daily handling (control) or 2 or 4 weeks of UCMS. Female mice displayed a more severe altered phenotype than males, as shown by increased anxiety- and depressive-like behaviors and deficits in PFC-dependent cognitive abilities, particularly after exposure to 2 weeks of UCMS. This behavioral phenotype was paralleled by a large increase in prefrontal PV messenger RNA (mRNA) and number of PV-expressing neurons, supporting our previous findings. We further showed that the expression of pre- and postsynaptic markers of glutamatergic transmission (VGlut1 presynaptic terminals and pERK1/2, respectively) onto PV neurons was increased by 2 weeks of UCMS in a sex-specific manner; this was associated with sex-specific changes in the mRNA expression of the NR2B subunit of the NMDA receptor. These findings provide evidence of increased glutamatergic transmission onto prefrontal PV neurons, particularly in female mice, which could potentially contribute to their increased PV expression and the extent of their behavioral impairment following UCMS. Finally, our analysis of activity of subcortical regions sending glutamatergic afferents to the PFC reveals that glutamatergic neurons from the basolateral amygdala might be specifically involved in UCMS-induced changes in prefrontal glutamatergic transmission.

Assessment of the acquisition of executive function during the transition from adolescence to adulthood in male and female mice.

Executive functions (EF) reached full maturity during the transition from adolescence to adulthood. Human studies provide important information about adolescent developmental trajectories; however, little remains known about the neural circuits underlying the acquisition of mature EF. Ethical and technical considerations with human subjects limit opportunities to design experimental studies that allows for an in-depth understanding of developmental changes in neural circuits that regulate cognitive maturation. Preclinical models can offer solutions to this problem. Unfortunately, current rodent models of adolescent development have inherent flaws that limit their translational value. For instance, females are often omitted from studies, preventing the assessment of potential sex-specific developmental trajectories. Furthermore, it remains unclear whether cognitive developmental changes in rodents are similar to those observed in humans. Here, we tested adolescent and adult male and female mice in a neurocognitive battery of assays. Based on this approach, we assessed mice performances within distinct subdomains of EF, and observed similarities with human developmental trajectories. Furthermore, the sex-specific cognitive changes we observed were paralleled by molecular and neural activity changes demonstrating that our approach can be used in future research to assess the contribution of precise neural circuits to adolescent cognitive maturation.

Modulation of neuroinflammation and pathology in the 5XFAD mouse model of Alzheimer's disease using a biased and selective beta-1 adrenergic receptor partial agonist.

Degeneration of noradrenergic neurons occurs at an early stage of Alzheimer's Disease (AD). The noradrenergic system regulates arousal and learning and memory, and has been implicated in regulating neuroinflammation. Loss of noradrenergic tone may underlie AD progression at many levels. We have previously shown that acute administration of a partial agonist of the beta-1 adrenergic receptor (ADRB1), xamoterol, restores behavioral deficits in a mouse model of AD. The current studies examined the effects of chronic low dose xamoterol on neuroinflammation, pathology, and behavior in the pathologically aggressive 5XFAD transgenic mouse model of AD. In vitro experiments in cells expressing human beta adrenergic receptors demonstrate that xamoterol is highly selective for ADRB1 and functionally biased for the cAMP over the ß-arrestin pathway. Data demonstrate ADRB1-mediated attenuation of TNF-α production with xamoterol in primary rat microglia culture following LPS challenge. Finally, two independent cohorts of 5XFAD and control mice were administered xamoterol from approximately 4.0-6.5 or 7.0-9.5 months, were tested in an array of behavioral tasks, and brains were examined for evidence of neuroinflammation, and amyloid beta and tau pathology. Xamoterol reduced mRNA expression of neuroinflammatory markers (Iba1, CD74, CD14 and TGFß) and immunohistochemical evidence for microgliosis and astrogliosis. Xamoterol reduced amyloid beta and tau pathology as measured by regional immunohistochemistry. Behavioral deficits were not observed for 5XFAD mice. In conclusion, chronic administration of a selective, functionally biased, partial agonist of ADRB1 is effective in reducing neuroinflammation and amyloid beta and tau pathology in the 5XFAD model of AD.

The transcription factor Npas4 contributes to adolescent development of prefrontal inhibitory circuits, and to cognitive and emotional functions: Implications for neuropsychiatric disorders.

The adolescent brain is marked by functional and structural modifications, particularly within the inhibitory system of the prefrontal cortex (PFC). These changes are necessary for the acquisition of adult cognitive functions and emotion regulation, and impairments in these processes are associated with neuropathologies such as schizophrenia and affective disorders. The molecular mechanisms regulating this adolescent refinement of prefrontal inhibitory circuits remain largely unknown. Here we demonstrate that the transcription factor Npas4 plays a major role in this process. Using a series of behavioral, molecular, pharmacological and genetic approaches in mice, we demonstrate that deficiency in Npas4 affects adolescent expression of multiple markers of GABAergic transmission in the PFC, including parvalbumin and GAD67, in a sex-specific manner. This abnormal pattern of expression of GABAergic markers is associated with sex-specific cognitive and emotional impairments that occur only when Npas4 deficiency begins at adolescence but not post-adolescence. Finally, we show that chronic treatment with the GABA enhancing drug sodium valproate during adolescence is sufficient to induce long-lasting recovery of the molecular and behavioral abnormalities observed in Npas4 deficient mice. Altogether, we provide evidence for the involvement of the transcription factor Npas4 to the structural changes that affect prefrontal inhibitory circuits during adolescence. Further investigations of Npas4 role in the adolescent brain might provide new insights on the molecular mechanisms underlying neuropsychiatric disorders that emerge during adolescence.

Sensitivity of the prefrontal GABAergic system to chronic stress in male and female mice: Relevance for sex differences in stress-related disorders.

Stress-induced modifications of the prefrontal cortex (PFC) are believed to contribute to the onset of mood disorders, such as depression and anxiety, which are more prevalent in women. In depression, the PFC is hypoactive; however the origin of this hypoactivity remains unclear. Possibly, stress could impact the prefrontal GABAergic inhibitory system that, as a result, impairs the functioning of downstream limbic structures controlling emotions. Preclinical evidence indicates that the female PFC is more sensitive to the effects of stress. These findings suggest that exposure to stress could lead to sex-specific alterations in prefrontal GABAergic signaling, which contribute to sex-specific abnormal functioning of limbic regions. These limbic changes could promote the onset of depressive and anxiety behaviors in a sex-specific manner, providing a possible mechanism mediating sex differences in the clinical presentation of stress-related mood disorders. We addressed this hypothesis using a mouse model of stress-induced depressive-like behaviors: the unpredictable chronic mild stress (UCMS) paradigm. We observed changes in prefrontal GABAergic signaling after exposure to UCMS most predominantly in females. Increased parvalbumin (PV) expression and decreased prefrontal neuronal activity were correlated in females with severe emotionality deficit following UCMS, and with altered activity of the amygdala. In males, small changes in emotionality following UCMS were associated with minor changes in prefrontal PV expression, and with hypoactivity of the nucleus accumbens. Our data suggest that prefrontal hypoactivity observed in stress-related mood disorders could result from stress-induced increases in PV expression, particularly in females. This increased vulnerability of the female prefrontal PV system to stress could underlie sex differences in the prevalence and symptomatology of stress-related mood disorders.

Npas4 deficiency increases vulnerability to juvenile stress in mice.

During specific windows of postnatal brain development, individuals are particularly susceptible to developing mental illnesses in adulthood. Adolescence is such a window during which environmental stress can have long-lasting consequences on social and cognitive functions. In individuals, highly vulnerable to stress, a relatively mild stressful situation can trigger the onset of psychiatric conditions. The genetic factors and mechanisms underlying vulnerability to stress are not well understood. Here, we show that variations in expression of the brain-specific transcription factor Npas4 contributes to the long-term consequences of juvenile stress on cognitive abilities. We observed that transgenic Npas4-deficient mice exposed to chronic mild stress during adolescence (but not during adulthood) develop prefrontal cortex-dependent cognitive deficits in adulthood, while the same stress did not affect Npas4 wild-type mice. These cognitive deficits were accompanied by fewer neuroblasts in the subventricular zone, and reduced ability of these immature neuronal cells to migrate away from this neurogenic zone toward cortical regions. These findings suggest for the first time that the transcription factor Npas4 could play a significant role in coping with juvenile stress. They also suggest that Npas4 could modulate resilience or vulnerability to stress by mediating the effects of stress on neurogenesis.